Publications Search - Abstract View
| Title: |
Association of LINE-1 Methylation With Risk of Bladder Cancer in the Spanish Population |
| Authors: |
Tajuddin SM, Amaral AFS, Fernandez AF, Moore L, Silverman DT, Kogevinas M, Rothman N, Real FX, Fraga MF, Malats N |
| Journal: |
European Journal of Cancer |
| Date: |
2012 Jul |
| Branches: |
OEEB |
| PubMed ID: |
|
| PMC ID: |
not available |
| Abstract: |
Background: A positive family history is an important risk factor for the development of breast cancer (BC). Mutations in the two major BC susceptibility genes, BRCA1 and BRCA2, account for only 20−25% of familial BC cases. More than 70% of hereditary cancers may thus be associated with mutations affecting other predisposing genes. The PALB2 protein (for Partner And Localizer of BRCA2) was described as a binding partner of BRCA2, essential for its function in double-strand break repair. Biallelic mutations in PALB2 gene cause Fanconi anemia subtype FA-N; heterozygous mutations in this gene predispose to BC. In familial BC, the PALB2 mutation frequency was estimated to be between 0.9−3.4% in different studies. The aim of our study was to determine the prevalence of PALB2 mutations among high-risk Czech breast/ovarian cancer patients. Material and Methods: We screened a total of 332 high-risk BRCA1/2-negative breast and ovarian cancer patients for PALB2 mutations using Sanger sequencing of the whole coding region of the gene. Analyzed group included 270 familial cases and 62 non-familial cases (bilateral BC, male BC, breast and ovarian tumor duplicity). Identified mutations were analyzed in a group of 1227 control samples. MLPA was used for the detection of large genomic rearrangements. Results: In total we found 10 different pathogenic mutations in 13 patients, whereas one mutation was observed in controls (P < 0.001). Twelve mutations were detected in 187 familial cases (6.4%) with a family history positive for BC only, whereas no mutation was detected in 83 families with ovarian cancer. One mutation was identified in 19 male BC cases (5.3%). Six frameshift and 3 nonsense mutations were identified by sequencing; MLPA technique revealed a large deletion including exons 9−10. Seven of the ten identified mutations were novel. A 4 base-pair deletion (c.172_175delTTGT) was found in four subjects and was the only recurrent mutation identified in the PALB2 gene. Analysis of this mutation was extended to a group of 704 unselected BC patients where it was identified in 2 cases (0.28%). Four of six carriers of this mutation shared the same haplotype suggesting a common origin of this mutation. Conclusion: Analysis of the PALB2 gene confirmed its role in BC susceptibility in the Czech population. High frequency of PALB2 mutations identified in high-risk BC families strongly suggests the relevance of clinical testing of this gene.Supported by grants: IGA MZCR 2012 |